Tasimelteon

Identification

Summary

Tasimelteon is a melatonin receptor agonist used to treat Non- 24-Hour Sleep-Wake Disorder.

Brand Names
Hetlioz
Generic Name
Tasimelteon
DrugBank Accession Number
DB09071
Background

Tasimelteon is a selective dual melatonin receptor agonist indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD). Occurring commonly in blind individuals without light perception, this condition is often characterized by periods of night-time insomnia and day-time sleepiness. In blind individuals, a lack of light stimulation causes an extension of the 24-hour circadian cycle and can lead to progressively delayed sleep onset. By activating melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, tasimelteon has been shown to improve sleep by resynchronizing the circadian rhythm through its "non-photic" mechanism. Tasimelteon is currently the only drug available for the treatment of N24HSWD and was granted orphan drug status by the FDA in 2010.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 245.322
Monoisotopic: 245.141578856
Chemical Formula
C15H19NO2
Synonyms
  • N-{[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanamide
  • Tasimeltéon
  • Tasimelteon
  • Tasimelteón
  • Tasimelteonum
External IDs
  • BMS 214778
  • BMS-214,778
  • BMS-214778
  • BMS214778
  • VEC 162
  • VEC-162
  • VEC162

Pharmacology

Indication

Tasimelteon is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (N24HSWD).

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2.

TargetActionsOrganism
AMelatonin receptor type 1A
agonist
Humans
AMelatonin receptor type 1B
agonist
Humans
Absorption

Not Available

Volume of distribution

The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L.

Protein binding

At therapeutic concentrations, tasimelteon is about 90% bound to proteins.

Metabolism

Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route.

Route of elimination

Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.

Half-life

The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours.

Clearance

Not Available

Adverse Effects
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Toxicity

The most common adverse reactions are headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infections. There are currently no adequate or well-controlled studies that suggest that tasimelteon is safe to use during pregnancy. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. During clinical trials, rats did not self-administer tasimelteon, suggesting that the drug does not have a potential for abuse.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Tasimelteon is combined with 1,2-Benzodiazepine.
AbacavirAbacavir may decrease the excretion rate of Tasimelteon which could result in a higher serum level.
AbametapirThe serum concentration of Tasimelteon can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Tasimelteon can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Tasimelteon.
AbirateroneThe serum concentration of Tasimelteon can be increased when it is combined with Abiraterone.
AcalabrutinibThe metabolism of Tasimelteon can be decreased when combined with Acalabrutinib.
AceclofenacAceclofenac may decrease the excretion rate of Tasimelteon which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Tasimelteon which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Tasimelteon.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of tasimelteon, which may increase its serum concentration. Alternatively, the dose of tasimelteon may need to be modified.
  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of tasimelteon and may reduce its serum concentration. Alternatively, the dose of tasimelteon may need to be modified.
  • Take on an empty stomach. The Cmax of tasimelteon is reduced when taken with food.

Products

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International/Other Brands
Hetlioz
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HetliozCapsule20 mg/1OralVanda Pharmaceuticals Inc.2014-04-04Not applicableUS flag
HetliozCapsuleOralVanda Pharmaceuticals Netherlands B.V.2016-09-08Not applicableEU flag
Hetlioz LQSuspension4 mg/1mLOralVanda Pharmaceuticals Inc.2020-12-10Not applicableUS flag

Categories

ATC Codes
N05CH03 — Tasimelteon
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as coumarans. These are compounds containing the coumaran skeleton, which consists of a benzene ring fused to a 2,3-dihydrofuran ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Coumarans
Sub Class
Not Available
Direct Parent
Coumarans
Alternative Parents
Alkyl aryl ethers / Benzenoids / Secondary carboxylic acid amides / Oxacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alkyl aryl ether / Aromatic heteropolycyclic compound / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Coumaran / Ether / Hydrocarbon derivative / Organic nitrogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid amide, 1-benzofurans, cyclopropanes (CHEBI:79042)
Affected organisms
Not Available

Chemical Identifiers

UNII
SHS4PU80D9
CAS number
609799-22-6
InChI Key
PTOIAAWZLUQTIO-GXFFZTMASA-N
InChI
InChI=1S/C15H19NO2/c1-2-15(17)16-9-10-8-13(10)11-4-3-5-14-12(11)6-7-18-14/h3-5,10,13H,2,6-9H2,1H3,(H,16,17)/t10-,13+/m0/s1
IUPAC Name
N-{[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanamide
SMILES
CCC(=O)NC[C@@H]1C[C@H]1C1=CC=CC2=C1CCO2

References

General References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]
  2. Neubauer DN: Tasimelteon for the treatment of non-24-hour sleep-wake disorder. Drugs Today (Barc). 2015 Jan;51(1):29-35. doi: 10.1358/dot.2015.51.1.2258364. [PubMed:25685859]
  3. Stahl SM: Mechanism of action of tasimelteon in non-24 sleep-wake syndrome: treatment for a circadian rhythm disorder in blind patients. CNS Spectr. 2014 Dec;19(6):475-8. doi: 10.1017/S1092852914000637. [PubMed:25422900]
  4. Vachharajani NN, Yeleswaram K, Boulton DW: Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist. J Pharm Sci. 2003 Apr;92(4):760-72. [PubMed:12661062]
KEGG Drug
D09388
PubChem Compound
10220503
PubChem Substance
310265003
ChemSpider
8395995
RxNav
1490468
ChEBI
79042
ChEMBL
CHEMBL2103822
ZINC
ZINC000004392649
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tasimelteon
FDA label
Download (249 KB)
MSDS
Download (203 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceNon-24-Hour Sleep-Wake Disorder / Non-24-Hour-Sleep-Wake Disorder1
3CompletedTreatmentInsomnia1
3CompletedTreatmentJet Lag Type Insomnia1
3CompletedTreatmentNon-24-Hour Sleep-Wake Disorder3
3CompletedTreatmentPrimary Insomnia1
3RecruitingTreatmentChronobiology Disorders / Sleep Disorders, Circadian Rhythm / Sleep Wake Disorders1
3Unknown StatusTreatmentNon 24 Hour Sleep Wake Disorder / Non-24-Hour Sleep-Wake Disorder1
2CompletedTreatmentCircadian Rhythm Sleep Disorders1
2CompletedTreatmentJet Lag Disorder1
2, 3CompletedTreatmentMajor Depressive Disorder (MDD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral20 mg/1
SuspensionOral4 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5856529No1999-01-052017-12-09US flag
US8785492No2014-07-222033-01-25US flag
US9060995No2015-06-232033-01-25US flag
US9549913No2017-01-242033-01-25US flag
US9539234No2017-01-102033-01-25US flag
US9730910No2017-08-152034-05-17US flag
USRE46604No2017-11-142033-01-25US flag
US9855241No2018-01-022033-01-25US flag
US10071977No2018-09-112035-02-12US flag
US10149829No2018-12-112033-01-25US flag
US10449176No2019-10-222033-01-25US flag
US10376487No2019-08-132035-07-27US flag
US10610510No2013-01-252033-01-25US flag
US10610511No2014-10-102034-10-10US flag
US10179119No2015-08-292035-08-29US flag
US10829465No2015-02-122035-02-12US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)442.553°CMSDS
water solubility1.1 mg/mLMSDS
logP2.43MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0381 mg/mLALOGPS
logP2.53ALOGPS
logP1.98ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)15.74ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.33 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity70.35 m3·mol-1ChemAxon
Polarizability27.52 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Organic cyclic compound binding
Specific Function
High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that ...
Gene Name
MTNR1A
Uniprot ID
P48039
Uniprot Name
Melatonin receptor type 1A
Molecular Weight
39374.315 Da
References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Melatonin receptor activity
Specific Function
High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that ...
Gene Name
MTNR1B
Uniprot ID
P49286
Uniprot Name
Melatonin receptor type 1B
Molecular Weight
40187.895 Da
References
  1. Lavedan C, Forsberg M, Gentile AJ: Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology. 2015 Apr;91:142-7. doi: 10.1016/j.neuropharm.2014.12.004. Epub 2014 Dec 19. [PubMed:25534555]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Ogilvie BW, Torres R, Dressman MA, Kramer WG, Baroldi P: Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist. J Clin Pharmacol. 2015 Sep;55(9):1004-11. doi: 10.1002/jcph.507. Epub 2015 May 7. [PubMed:25851638]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Ogilvie BW, Torres R, Dressman MA, Kramer WG, Baroldi P: Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist. J Clin Pharmacol. 2015 Sep;55(9):1004-11. doi: 10.1002/jcph.507. Epub 2015 May 7. [PubMed:25851638]
  2. Tasimelteon FDA label [File]

Drug created on May 14, 2015 16:07 / Updated on February 21, 2021 18:52